CMT 1A: MCP-1/CCL2 Modifies Axon Properties in a PMP22-Overexpressing Mouse Mode

[Guest guest]

Am J Pathol. 2010 Jan 21

MCP-1/CCL2 Modifies Axon Properties in a PMP22-Overexpressing Mouse Model for

Charcot-Marie-Tooth 1A Neuropathy.

Kohl B, Fischer S, Groh J, Wessig C, i R.

From the Department of Neurology, Section of Developmental Neurobiology,

University of Wuerzburg, Wuerzburg, Germany.

Charcot-Marie-Tooth 1A (CMT1A) neuropathy, the most common inherited peripheral

neuropathy, is primarily caused by a gene duplication for the peripheral myelin

protein-22 (PMP22). In an accordant mouse model, we investigated the role of

monocyte chemoattractant protein-1 (MCP-1/CCL2) as a regulator of nerve

macrophages and neural damage including axonopathy and demyelination. By

generating PMP22tg mice with reduced levels or lack of MCP-1/CCL2, we found that

MCP-1/CCL2 is involved in the increase of macrophages in mutant nerves. PMP22tg

mice with wild-type levels of MCP-1/CCL2 showed strong macrophage increase in

the diseased nerves, whereas either 50% reduction or total absence of MCP-1/CCL2

led to a moderate or a strong reduction of nerve macrophages, respectively.

Interestingly, MCP-1/CCL2 expression level and macrophage numbers were

correlated with features indicative of axon damage, such as maldistribution of

K(+) channels, reduced compound muscle action potentials, and muscle weakness.

Demyelinating features, however, were most highly reduced when MCP-1/CCL2 was

diminished by 50%, whereas complete lack of MCP-1/CCL2 showed an intermediate

demyelinating phenotype. We also identified the MEK1/2-ERK1/2-pathway as being

involved in MCP-1/CCL2 expression in the Schwann cells of the CMT1A model. Our

data show that, in a CMT1A model, MCP-1/CCL2 activates nerve macrophages,

mediates both axon damage and demyelination, and may thus be a promising target

for therapeutic approaches.